Central nervous system injuries, including injuries to the spinal cord, are among the most devastating and disabling injuries possible. Depending upon the severity of the injury, paralysis of varying degrees can result. Paraplegia and quadriplegia often result from severe injury to the spinal cord.
The worldwide annual incidence of spinal cord injury (SCI) is estimated at 22 persons per million and the total number of SCI survivors is estimated at 2.5 million. SCI most often occurs in people in their mid-twenties who can anticipate a quasi-normal life expectancy albeit with challenges to maintain an acceptable quality of life. This generates important personal, societal, and economic costs. Although life expectancy is very good, SCI patients suffer from some important handicaps (depending on the level and severity of the lesion) that seriously diminish their quality of life (e.g., paralysis, sensory loss, intractable pain, pressure sores, and urinary and other infections). Despite the intensive work that has been invested by the scientific and clinical communities during the last two decades, there is as yet no cure or treatment that can reverse lost functions after SCI.
To date, the therapeutic efforts focused mainly on preventing the destructive events (neuroprotection) and less on augmenting the spontaneous repair events evoked by SCI. Further recovery of function will require a combination of effective neuroprotective and restorative therapeutic interventions. The above considerations have led the inventors to follow a novel physiological approach that employs the body's professional healing system, the immune system, to contend with the consequences of central nervous system (CNS) damage leading to neuroprotection and restoration.
It was shown in the laboratory of the inventors that blood-derived monocytes incubated with skin segments acquired a non-inflammatory phenotype similar to anti-inflammatory M2 monocytes described in the literature (Bomstein et al., 2003). Injection of the monocytes into the injured spinal cord induced better recovery from SCI in rats (U.S. Pat. No. 5,800,812; U.S. Pat. No. 6,117,424; and U.S. Pat. No. 6,267,955). This approach was tested in a clinical study on patients suffering from acute sever spinal cord injury showing encouraging results (WO 03/044037; Knoller et al., 2005). Accordingly, the treatment required a surgical procedure including laminectomy to expose the injured spinal cord and injection of the cells to the borders of the lesion site, which was difficult to allocate. The inventors felt that finding ways to overcome the difficulty of allocating the site of lesion and the exposure of patients to an invasive procedure would be helpful in the treatment of SCI.
More recent research performed in the laboratory of the inventors showed that following spinal cord injury, at three to four days post injury blood born monocytes spontaneously infiltrate to the damaged CNS, preferentially accumulate at the margins of the lesion site and play a pivotal role in the process of recovery. These cells modulate the immune activity at the injured tissue to become less inflammatory, and produce molecules that support healing, and thus favorable for cell renewal and tissue repair (Shechter et al., 2009). Despite their positive role, in severe injuries it was insufficient to induce a full recovery or even partial functional recovery.
Infiltration/recruitment of peripheral blood into the lesion site is controlled by signals elicited from the lesion site, which affects the brain-CSF barrier. The limited spontaneous recovery following CNS injury can be attributed in part to the inadequate, untimely, spontaneous recruitment of the effective subset of monocytes to the lesion site. In line with this, we have shown that enrichment of peripheral blood monocytic pool with bone-marrow derived CD115 cells augmented functional recovery following SCI in mice (Shechter et al., 2009).
Blood monocytes are heterogenic cellular population with different characteristics and activities. Utilizing blood monocytes for therapeutic purposes requires the identification of the cells with harmful functions and those that are beneficial.
In humans, it was proposed that the expression of CD16 on monocytes can distinguish between three subsets, namely CD14++CD16− (classical) CD14++CD16++ and CD14dimCD16++ (non-classical) monocytes, but their role in physiological and pathological conditions is not fully understood.